JP2012526802A - Method for producing alkylamine derivative - Google Patents

Abstract

The present invention provides a method for producing an alkylamine derivative that is almost free of impurities and is highly pure and capable of mass production.

Description

  The present invention relates to a production method that enables an alkylamine derivative to be produced in high purity and in large quantities using an acid during hydrolysis of a dialkylamino ester hydrochloride.

A compound in which R ₁ and R ₂ are all methyl groups in the following chemical formula 1 having four carbons as a basic skeleton is a drug represented by chemical formula II (HKI-272, Neratinib) and chemical formula as shown in reaction formula 1. It can be used very effectively for the production of a pharmaceutical represented by III (BIBW-2992, Tovok).

... (Chemical formula 1)

In the above formula, R ₁ and R ₂ each independently represent an alkyl group having 1 to 2 carbon atoms, and compounds having the same methyl group are preferred.

... (Reaction formula 1)

... (Reaction formula 2)

  As shown in Reaction Schemes 1-2 above, the compound of Formula 1 is used in the manufacture of pharmaceuticals of Formulas II and III in the form of hydrochloride. The compounds of the above formulas II and III are HER-2 Tyrosine Kinase Inhibitor, which is used as an anticancer agent exhibiting pharmacological activity, and is known as a compound having superior side effect contrast efficacy than other existing compounds (US 003 / 050222A1, US 2004/0162442 A1, US 7,126,025, B2)

  However, the compound of Formula 1 is a very interesting and useful compound industrially and academically due to many restrictions in production. Therefore, it is necessary to develop a new method for mass-producing the compound of Chemical Formula 1.

  However, as a conventional method for producing the compound of Chemical Formula 1, there is no technology that can be industrially mass-produced except for the following Reaction Formula 3 (US7, 126, 025, B2).

... (Reaction formula 3)

  That is, since the compound of the above chemical formula 1 can only be produced by the currently known method represented by the above reaction formula 3, unless carbon tetrachloride or benzene, which is extremely toxic to the human body, is used as a solvent. There is a problem that must not be. At the same time, the above method has a risk of explosion during the reaction due to the unavoidable disadvantage of the reaction. Therefore, the existing production method of Chemical Formula 1 is extremely limited due to the above-mentioned problems, and only a method in which mass production is very difficult industrially is known.

  In addition, the existing production method of Chemical Formula 1 has a fatal problem in which a large amount of impurities cannot be avoided. The compound of Chemical Formula 1 produced using this method contains a large amount of impurities. Become. Therefore, when the physiologically active substance of Chemical Formulas II and III is produced using the compound of Chemical Formula 1 produced by the above method, the amount of raw materials and auxiliary materials input varies greatly depending on each reaction in the production process. In addition, as a result, it is necessary to produce compounds of chemical formulas II and III containing a large amount of impurities, and if it does not pay a great deal of economic expenses for the purification process after the chemical reaction, it has value as the intended pharmaceutical product. The target compound cannot be obtained.

  Moreover, if the compound of Chemical Formula 1 is produced by the process of Reaction Formula 3, the target compound can be obtained, but the equivalent amount required during the reaction cannot be predicted, so that many by-products are generated. Become. The method for removing the by-product uses a physical recrystallization method or the like. However, since the structure of the generated impurity is very similar to that of the compound of Chemical Formula 1, the economic cost of removing this by-product. Becomes excessive. However, the actual situation is that no method for producing or purifying impurities below the level required by pharmaceutical quality standards has been found.

  In other words, as shown in Reaction Formula 3, when the ester is hydrolyzed with a base after the introduction of an amine group after proceeding with a bromination reaction, it cannot be used in pharmaceutical production requiring a strict impurity level. . Also, as shown in Reaction Scheme 3, when the ethyl ester is hydrolyzed using a base, 4-dimethylamino-3-hydroxybutyric acid (hereinafter, norcarnitine) hydrochloride having a hydroxyl group added at the 3-position is obtained. It is a fatal disadvantage that chemical formula 1 which is a desired high-purity target compound cannot be obtained together with the bis-impurity which is produced in a large amount as an impurity and is introduced when an amine group is introduced.

  Therefore, the present invention has been made in view of the above-described problems of the prior art, and the object of the present invention is to produce norcarnitine, which is an impurity, using an acid during hydrolysis of dialkylamino ester hydrochloride. It is an object of the present invention to provide a method for producing an alkylamine derivative that suppresses the maximal effect.

  Another object of the present invention is to chemically change the bis-impurity generated at the time of introduction of the amine group into the target compound to obtain the chemical formula 1 which is a high-purity target compound used in pharmaceuticals of formulas II and III. An object of the present invention is to provide a method for producing an alkylamine derivative that can be produced.

  Furthermore, another object of the present invention is to provide a method for producing an alkylamine derivative that is mild in reaction conditions, capable of mass production, and economical.

In order to achieve the above object, the present invention includes a step of hydrolyzing a _C1-4 alkyl 4-dialkylaminocrotonic acid ester hydrochloride in the presence of an acid to produce 4-dialkylaminocrotonic acid hydrochloride. A method for producing an alkylamine derivative is provided.

The C _1-4 alkyl 4-dialkylaminocrotonic acid ester hydrochloride is preferably ethyl 4-dimethylaminocrotonic acid ester hydrochloride.

  The acid during the hydrolysis may be hydrochloric acid, sulfuric acid, benzenesulfonic acid, benzenesulfonic acid substituted with a methyl group, carboxylic acid, alkyl carboxylic acid having 1 to 3 carbon atoms, phenylcarboxylic acid, phosphoric acid, bromic acid or Preference is given to using iodic acid.

  In addition, the 4-dialkylaminocrotonic hydrochloride is preferably a compound represented by the following chemical formula 1.

... (Chemical formula 1)

In the above formula, R ₁ and R ₂ each independently represent an alkyl group having 1 to 2 carbon atoms, and are preferably the same methyl group.

  The present invention suppresses the production of norcarnitine, which is an impurity, using an acid at the time of hydrolysis of dialkylamino ester hydrochloride, and chemically changes the bis impurity produced at the time of amine group introduction to the target compound. There is an effect of providing a method for producing an alkylamine derivative capable of producing Chemical Formula 1, which is a high-purity target compound that can be used for pharmaceuticals of Chemical Formulas II and III.

Hereinafter, the present invention will be described in more detail.
The present invention relates to a method for producing an alkylamine derivative capable of suppressing the generation of impurities during hydrolysis and chemically changing a bis compound produced during an amination reaction to a target compound. Therefore, the present invention is not only industrially useful and facilitates mass production, but also economically efficient 4-dialkylaminocrotonic hydrochloride of formula 1 which is the target compound under mild reaction conditions. It relates to a method of manufacturing.

  In general, in order to produce the compound represented by the chemical formula 1, production of a high purity bromine compound and hydrolysis reaction are required. However, in the case of the conventional method, since a base is used in the hydrolysis process, a large amount of impurities such as norcarnitine is generated, and the bisimpurities that cannot be avoided during the amination reaction are not removed in the recrystallization process. It was difficult to produce a pure compound of formula 1.

  That is, even when hydrolysis is performed at a low temperature using a base such as caustic soda, lithium hydroxide, or calcium hydroxide during the hydrolysis, about 30% or more of norcarnitine is produced as an impurity. Therefore, the present invention can reduce the production ratio of norcarnitine produced as an impurity during hydrolysis to 3% or less by using an acid catalyst to prevent this. In addition, if a base such as caustic soda is used, the 3,4-bis (trialkylamino) butyric acid ethyl ester produced during the amination reaction is the target 4-dialkylaminocrotonic acid hydrochloride of Formula 1. However, the reaction is terminated with 3,4-bis (trialkylamino) butyric acid, and the compound of formula 1 as the target compound cannot be obtained with a purity of 99% or more.

Accordingly, in order to solve the above problems, the present invention provides a process for producing 4-dialkylaminocrotonic acid hydrochloride by hydrolyzing _C1-4 alkyl 4-dialkylaminocrotonic acid ester hydrochloride in the presence of an acid. An alkylamine derivative can be produced.

  By such a method, the alkyl 3,4-bis (trialkylamino) butyric acid ester produced by the amination reaction is not terminated with 3,4-bis (trialkylamino) butyric acid. In addition, 4-dialkylamino-3-hydroxybutyric acid hydrochloride is 3% or less in 4-dialkylaminocrotonic acid hydrochloride by hydrolysis, and 3,4-bis (trialkylamino) butyric acid dihydrochloride is It will be present at 0.1% or less. Therefore, the present invention can obtain 4-dialkylaminocrotonic acid hydrochloride with a high purity of 99.5% or more and a yield of 70% or more, and thus can be mass-produced more economically than before. .

At this time, the C _1-4 alkyl 4-dialkylaminocrotonic acid ester hydrochloride is produced by brominating an alkyl 4-hydroxycrotonic acid ester to produce a brominated compound, and aminating it. Can do.

  In addition, the 4-dialkylaminocrotonic hydrochloride is preferably a compound represented by the following chemical formula 1.

... (Chemical formula 1)

In the above formula, R ₁ and R ₂ each independently represent an alkyl group having 1 to 2 carbon atoms, and are preferably the same methyl group.

  Hereinafter, the production method of the present invention will be described more specifically with reference to the following reaction formula 4.

... (Reaction formula 4)

In said formula, R < ₁ > and R < ₂ > represents a methyl group or an ethyl group each independently, and R < ₃ > represents a C1-C4 alkyl group.

  As shown in the above reaction scheme 4, the present invention can be obtained by treating an alkyl 4-chloro-3-hydroxybutyrate ester of the chemical formula (5) with anhydrous ethanol with caustic soda, and a pure alkyl 4-hydroxy of the chemical formula (4). -A crotonic acid ester can be obtained (Step 1).

  Next, according to the present invention, a purely produced crotonic acid ester of the chemical formula (4) is brominated and then purified by distillation under reduced pressure to obtain a high purity bromine compound of the chemical formula (3). (Step 2).

  The bromination reaction is performed under conditions using triphenylphosphine bromine salt. At this time, the triphenylphosphine bromine salt used as the bromination reagent may be one produced by reaction of triphenylphosphine with bromine or N-bromosuccinimide.

In the bromination reaction, a C ₁ -C ₈ alkylsulfonyl chloride or a C ₀ -C ₁ substituted benzenesulfonyl chloride was reacted with an alkyl 4-hydroxycrotonate to produce a sulfonate compound. Later, an inorganic or organic bromine salt such as metal bromide or quaternary alkyl ammonium bromide can be reacted to produce alkyl 4-bromocrotonate.

At this time, the C ₁ -C ₈ alkylsulfonyl chloride is preferably methanesulfonyl chloride. The C ₀ -C ₁ substituted benzenesulfonyl chloride is benzenesulfonyl chloride or methylbenzenesulfonyl chloride. The metal bromide or quaternary alkylammonium bromide is sodium bromide, potassium bromide, calcium bromide, lithium bromide, tetramethylammonium bromide, tetrabutylammonium bromide or tetraethylammonium bromide. 1 to 2 equivalents can be used as a mixture.

The bromination reaction can be performed with an organic solvent used for organic synthesis such as methylene chloride, THF, DMF, etc., usually at a low temperature of 0 ° C.
After the reaction of Step 2, the present invention proceeds with an amination reaction for the brominated compound of Formula (3) to produce an ester hydrochloride compound of Formula (2) having a dialkylamino group at the 4-position. Yes (Step 3).

The amination reaction proceeds by slowly adding dialkylamine dissolved in an organic solvent, preferably dimethylamine, dropwise at a low temperature of 2 to 2.5 equivalents to a bromine compound solution of Formula (3) dissolved in an organic solvent. be able to. Thereafter, a _C1-4 alkyl 4-dialkylaminocrotonic acid ester hydrochloride of the chemical formula (2) can be obtained purely using an ethyl acetate hydrochloric acid solution as the reaction product.

  At this time, the amination reaction may produce a 3,4-bis (trialkylamino) butyric acid ethyl ester compound together with the compound of the chemical formula (2), which can be removed through a subsequent hydrolysis reaction. Specifically, 3,4-bis (trimethylamino) butyric acid ethyl ester can be produced by the reaction with dimethylamine.

At this time, not only the ethyl acetate hydrochloric acid solution but also a normal alkyl acetate hydrochloric acid solution such as a methyl acetate hydrochloric acid solution can be used as the compound used for the preparation of the hydrochloride.
The organic solvent may be any organic solvent such as methylene chloride, THF, DMF, etc., as long as it is used for ordinary organic synthesis, and the kind thereof is not particularly limited. The amination reaction is preferably performed at a temperature of −10 ° C. or higher and 10 ° C. or lower.

  Next to Step 3, the present invention obtains 4-dialkylaminocrotonic acid hydrochloride of the chemical formula (1) by hydrolyzing the obtained alkyl 4-dialkylaminocrotonic acid ester hydrochloride of the chemical formula (2) with an acid. Can do. In particular, according to the present invention, by using an acid during hydrolysis, norcarnitine can be produced to 3% or less, and the content of impurities can be minimized. In the present invention, 3,4-bis (trialkylamino) butyric acid ester is a desired target compound by hydrolyzing an ester group with a compound of chemical formula (2) using an acid catalyst or an acid. It is characterized by being converted to 4-dialkylaminocrotonic acid of (1).

  Therefore, according to the method of the present invention, 4-dimethylamino-3-hydroxybutyric acid hydrochloride which is 10% or less norcarnitine as an impurity is produced by hydrolysis. In addition, since 3,4-bis (trialkylamino) butyric acid dihydrochloride is removed by the hydrolysis, the content of 4-dimethylamino-3-hydroxybutyric acid hydrochloride generated as an impurity is 3%. Limited to: Therefore, 0.1% or less of 3,4-bis (trialkylamino) butyric acid dihydrochloride remains as the impurity. In addition, the impurity can be produced only by 3% or less of 4-dimethylamino-3-hydroxybutyric acid hydrochloride. In addition, 3,4-bis (trialkylamino) butyric acid dihydrochloride is removed through recrystallization after hydrolysis. Thereby, the content of 4-dimethylamino-3-hydroxybutyric acid hydrochloride is reduced to 0.1% or less, and 4-dialkyl in which 3,4-bistrimethylaminobutyric acid dihydrochloride is present in 0.02% or less Aminocroton hydrochloride can be prepared. Thus, in the present invention, the hydrochloride salt of 4-dialkylaminocrotonic acid, which is a pure target compound, can be obtained with a high purity of 99.5% or more.

At this time, the hydrolysis can be performed using water and a small amount of an acid catalyst. If crystallization proceeds with isopropanol after hydrolysis, pure 4-dialkylaminocrotonic acid hydrochloride is converted to 99.5% or more. And a yield of 70% or more.
The acid during the hydrolysis may be hydrochloric acid, sulfuric acid, benzenesulfonic acid, benzenesulfonic acid substituted with a methyl group, carboxylic acid, alkyl carboxylic acid having 1 to 3 carbon atoms, phenylcarboxylic acid, phosphoric acid, bromic acid or Preference is given to using iodic acid. Preferably, hydrochloric acid is used because it does not require a separate step of removing the acid catalyst.

The amount of the acid used is 1.05 to 10 equivalents, more preferably 1.1 to 1.2 equivalents, relative to C _1-4 alkyl 4-dialkylaminocrotonic acid ester hydrochloride. At this time, if hydrolysis is performed under conditions where the acid content range deviates from the range of the present invention, norcarnitine is excessively produced and is removed to 0.1% or less by an economical method in the crystallization stage. Is impossible.

  Moreover, although the said hydrolysis can be performed at the temperature of 50-110 degreeC, Preferably it hydrolyzes at 90-105 degreeC. If the temperature at the time of hydrolysis is less than 50 ° C., the bis-impurity removal reaction does not occur during the ester hydrolysis reaction. In addition, raising the temperature to 110 ° C. or higher is not economically desirable because excessive heat energy is used. However, since the process time for converting the bis impurity to the target compound and the formation reaction of norcarnitine is fast and the amount may be 3% or more during hydrolysis, the temperature range is 90-105 ° C. It is better to adjust.

  In the method of the present invention as described above, most preferably, after reacting ethyl 4-dimethylaminocrotonate with an aqueous solution at 90 to 105 ° C. using a hydrochloric acid catalyst, a 4-dialkylaminocroton is obtained by a recrystallization method. Producing 4-dialkylaminocrotonic hydrochloride in which 4-dimethylamino-3-hydroxybutyric acid hydrochloride and 3,4-bistrimethylaminobutyric acid dihydrochloride salt are present in 0.02% or less in hydrochloric acid salt including.

  Since the compound of Formula 1 prepared by such a method has almost no impurities, the purification process can be minimized when used in the manufacture of pharmaceuticals (HKI-272, BIBW-2992, etc.).

  Hereinafter, preferred examples will be presented for understanding of the present invention. However, the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited by the following examples.

... (Reaction formula 4-1)

[Step 1]
A 3 L one-neck flask was charged with ethyl 4-chloro-3-hydroxybutyrate (200 g, 1.2 mol) and absolute EtOH (1200 mL) and added to absolute EtOH (800 mL). Completely dissolved NaOH (52.8 g, 1.1 eq) solution was added slowly at 0 ° C. After all the NaOH solution was added, the temperature was naturally raised to room temperature and stirred for about 15 hours. When the reaction was completed, AcOH (69 mL, 1 eq) was added and stirred for 10 minutes, and then concentrated to remove EtOH.

Methylene chloride (1 L) and water (1 L) were added to the concentrate for extraction, and then the aqueous layer was extracted twice with methylene chloride (1 L). The organic layer was collected, washed with saturated NaHCO ₃ (600 mL), dried over anhydrous MgSO ₄ , filtered and concentrated to obtain 133 g of (E) -ethyl 4-hydroxybut-2-enoate in 85% yield. It was.
¹ H-NMR (δ ppm, CDCl ₃ , 400 Mz): 6.95 (m, 1H), 6.00 (m, 1H), 4.25 (m, 2H), 4.10 (q, 2H), 1 .20 (t, 3H)

[Step 2]
Triphenylphosphine (295 g, 1.12 mol) and methylene chloride (665 mL) were placed in a 3 L one-neck flask and stirred at 0 ° C. for 10 minutes. Then bromine (179.3 g) dissolved in methylene chloride (665 mL) was slowly added dropwise over 1 hour. At this time, the temperature of the reactor was maintained at 0 ° C. After all the bromine was added dropwise, the reaction was further stirred for 30 minutes. (E) -ethyl 4-hydroxybut-2-enoate (133 g, 1.02 mol) dissolved in methylene chloride (665 mL) was slowly added dropwise to the reaction mixture for 1 hour. At this time, the temperature of the reactor must also be maintained at 0 ° C. (E) -ethyl 4-hydroxybut-2-enoate was added dropwise, and the mixture was further stirred at 0 ° C. for 30 min (reaction confirmed by TLC, EtOAc: hexane = 1: 4). After washing the organic layer of the reaction product with water (900 mL × 2), the organic layer is dried over anhydrous MgSO ₄ and then concentrated by filtration to precipitate a large amount of Ph 3 P═O together with the product. After adding n-hexane (1 L), the mixture was stirred with a mechanical stirrer for 30 minutes and then filtered to remove triphenylphosphine oxide. The filtrate was concentrated under reduced pressure, and the concentrated solution was vacuum distilled to obtain 160 g of (E) -ethyl 4-bromobut-2-enoate with a yield of 81.2%.
¹ H-NMR (δ ppm, CDCl ₃ , 400 Mz): 6.92 (m, 1H), 5.95 (m, 1H), 4.15 (q, 2H), 3.95 (m, 2H), 1 .25 (t, 3H)

[Step 3]
(E) -ethyl 4-bromobut-2-enoate (160 g, 0.83 mol) and methylene chloride (1.6 L) were placed in a 5 L three-neck flask and stirred at −10 ° C. for 10 minutes. Extract 50% Me ₂ NH (187.1 g, 2.5 eq) with methylene chloride (1.6 L) and discard the aqueous layer during extraction. Thereafter, a Me ₂ NH solution dissolved in methylene chloride was slowly added dropwise to the flask for 1 hour. At this time, the internal temperature of the reactor was maintained at 5 ° C. or lower. After all of the Me ₂ NH solution dissolved in methylene chloride was added dropwise, the progress of the reaction was confirmed by TLC and stirred until no starting material was seen. Stirring takes about 30 minutes and care is taken not to increase the reaction time. Water (1280 mL) was added to the reaction solution. The reaction mixture was separated using a separatory funnel, and then the organic layer was mixed with an aqueous base solution (a solution of NaOH (66.4 g, 2 eq) dissolved in water (830 mL) and a brine solution (800 mL) were used in advance). Washed with. The separated organic layer was dried over anhydrous MgSO 4 and concentrated by filtration. The concentrated solution was transferred to a 2 L two-neck flask and dissolved in EtOAc (1380 mL), and then an EtOAc solution (222 mL, 1.2 eq) in which 4.5 M HCl was dissolved was slowly added dropwise. After the reaction vessel temperature dropped to room temperature, the reaction mixture was filtered through a filter and the remaining solid in the filter was washed with EtOAc (500 mL). The solid was transferred to one-neck and then dried with a vacuum device to obtain 128.6 g of (E) -ethyl 4- (dimethylamino) but-2-enoate hydrochloride 80% in yield.
¹ H-NMR (δ ppm, D ₂ O, 400 Mz): 6.85 (m, 1H), 6.23 (m, 1H), 4.15 (q, 2H), 4.90 (d, 2H), 2.85 (s, 6H), 1.25 (t, 3H)

[Step 4]
(E) -ethyl 4- (dimethylamino) but-2-enoate hydrochloride (20 g, 0.103 mol) was dissolved in water (102 mL) in a 250 mL two-neck flask, and then conc. HCl (2.6 mL) was added. After the reaction mixture was refluxed for 3 hours, the reaction mixture was cooled to room temperature. EtOH generated during the reaction was removed by distillation under reduced pressure, and water (34 mL) was added. Further conc. After addition of HCl (1.3 mL), the reaction mixture was refluxed for an additional 2 hours and water was removed from the reaction mixture by vacuum distillation. IPA (100 mL) was added to the remaining solid and recrystallized. During recrystallization, the IPA solution was heated at 40 to 50 ° C. and stirred at room temperature for 2 hours. The produced solid was filtered with a filter, and the solid was washed with IPA (10 mL). The obtained solid was collected and dried to obtain 12 g of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride in a yield of 70%. (99.8% Purity by HPLC, Corona Detector)
¹ H-NMR (δ ppm, D ₂ O, 400 Mz): 6.95 (m, 1H), 6.30 (m, 1H), 4.00 (m, 2H), 2.9d (s, 6H)

Comparative example

  Step 1 to Step 3 were performed in the same manner as in the example, and Step 4 was performed as follows instead of Step 4 in the example.

  That is, (E) -ethyl 4- (dimethylamino) but-2-enoate hydrochloride 16 g produced in Step 3 of Example 1 was dissolved in 100 mL of water, and then 16 g of 50% aqueous sodium hydroxide solution was kept at 5 ° C. or less for 1 hour. Slow addition was carried out and hydrolysis was carried out at the same temperature for 2 hours. The reaction solution was adjusted to pH 7 using hydrochloric acid, the aqueous solution was removed, and the ratio of norcarnitine produced by NMR was confirmed. After carrying out the reaction at −20 ° C. or lower under the same conditions, the pH was adjusted to 7, the aqueous solution was removed, and the ratio of norcarnitine produced by NMR was confirmed. The analysis was carried out by performing the same reaction using lithium hydroxide and calcium hydroxide under the above two temperature conditions.

Norcarnitine: ¹ H-NMR (D ₂ O, δ ppm, 400 Mz): 4.35 (m, 1H), 3.20 (m, 2H), 2.91 (s, 6H), 2.45 (d, 2H)
Bis impurity: ¹ H-NMR (D ₂ O, δ ppm, 400 Mz): 4.25 (m, 1H), 3.71 (m, 2H), 3.15 (m, 2H), 3.09 (s, 6H), 2.96 (s, 2H)

  As a result of NMR confirmation, it was confirmed that norcarnitine showing the above NMR pattern was produced in an amount of 30% or more relative to the target compound in the reaction under 6 conditions using a base. Moreover, the bis impurity produced | generated by Step3 to 5% or less showed the NMR form from which only the ethyl ester was hydrolyzed. This means that if a base is used, a large amount of norcarnitine is produced and bis impurities cannot be removed.

Claims (19)

A process for producing an alkylamine derivative comprising the step of hydrolyzing C _1-4 alkyl 4-dialkylaminocrotonic acid ester hydrochloride in the presence of an acid to produce 4-dialkylaminocrotonic acid hydrochloride. The method of claim 1, wherein the C _1-4 alkyl 4-dialkylaminocrotonate hydrochloride is ethyl 4-dimethylaminocrotonate hydrochloride. Examples of the acid include hydrochloric acid, sulfuric acid, benzenesulfonic acid, benzenesulfonic acid substituted with a methyl group, carboxylic acid, alkyl carboxylic acid having 1 to 3 carbon atoms, phenylcarboxylic acid, phosphoric acid, bromic acid or iodic acid. The method of claim 1. The method of claim 3, wherein the acid uses hydrochloric acid. The method according to claim 4, wherein the acid is used in an amount of 1.05 to 10 equivalents relative to C _1-4 alkyl 4-dialkylaminocrotonate hydrochloride. The method according to claim 5, wherein the acid is used in an amount of 1.1 to 1.2 equivalents based on 4-dialkylaminocrotonic acid ester hydrochloride. The method according to claim 1, wherein the hydrolysis is performed at a temperature of 50 to 110 ° C. The process according to claim 1, wherein 0.1% or less of 3,4-bistrimethylaminobutyric acid dihydrochloride remains after the hydrolysis. The method of claim 1, wherein the method produces 10% or less of 4-dimethylamino-3-hydroxybutyric acid hydrochloride as an impurity by hydrolysis. 10. The method of claim 9, wherein the method produces only 3% or less of 4-dimethylamino-3-hydroxybutyric acid hydrochloride as an impurity by hydrolysis. The method according to claim 9, wherein the method leaves only 0.1% or less of 4-dimethylamino-3-hydroxybutyric acid hydrochloride as an impurity through recrystallization after hydrolysis. The method according to claim 1, wherein the method produces 4-dialkylaminocroton hydrochloride with a purity of 99.5% or more. 2. The method according to claim 1, wherein the alkyl 4-dialkylaminocrotonate hydrochloride is prepared by subjecting an alkyl 4-hydroxycrotonate to a bromination reaction to produce a brominated compound and an amination reaction thereof. . 14. The method of claim 13, wherein the bromination reaction is performed using triphenylphosphine bromine salt. The method according to claim 14, wherein the triphenylphosphine bromine salt is produced by reacting triphenylphosphine with bromine or bromosuccinimide. In the bromination reaction, a C ₁ -C ₈ alkylsulfonyl chloride or a C ₀ -C ₁ substituted benzenesulfonyl chloride and an alkyl 4-hydroxycrotonate are reacted to produce a sulfonate compound, and then a metal bromide or The method according to claim 13, wherein the quaternary alkyl ammonium bromide is reacted to produce an alkyl 4-bromocrotonate. Wherein C ₁ -C ₈ alkylsulfonyl chloride is methane sulfonyl chloride The method of claim 16. The metal bromide or quaternary alkylammonium bromide is sodium bromide, potassium bromide, calcium bromide, lithium bromide, tetramethylammonium bromide, tetrabutylammonium bromide or tetraethylammonium bromide. The method according to claim 16, wherein one or more of them are used in an equivalent amount. In the above method, ethyl 4-dimethylaminocrotonate is reacted with an aqueous solution at 90 to 105 ° C. using a hydrochloric acid catalyst, and then 4-dimethylamino-3 in 4-dialkylaminocrotonic acid hydrochloride by a recrystallization method. The process according to claim 1, wherein 4-dialkylaminocroton hydrochloride is produced in which -hydroxybutyric acid hydrochloride and 3,4-bistrimethylaminobutyric acid dihydrochloride are present in 0.02% or less.